The purpose of this project is to elucidate the principles of treatment of chronic pain syndromes that are considered resistant to conventional treatment, such as pain caused by peripheral neuropathy and nerve injury, and by advanced cancer. In a randomized, double-blind, crossover study, 20 patients each with diabetic neuropathy and post-herpetic neuralgia were treated with 6 weeks etch of placebo and desipramine, an antidepressant that selectively blocks synaptic reuptake of norepinephrine. An interim analysis of the first 14 diabetics who completed the study showed that desipramine was superior to placebo in relieving pain, land caused fewer side-effects than had been observed in previous studies with amitriptyline, the standard medication. In another study, 20 patients with neuropathic pain showed no analgesic response to single doses of two serotonin agonists, buspirone and mCPP. These results support the hypothesis that the potentiation of noradrenergic neural activity is sufficient to inhibit some neuropathic pain states, and that acute stimulation of serotonergic receptors may not be sufficient for analgesia. To directly examine these questions, a comparison of amitriptyline, desipramine, and fluoxetine (a specific blocker of serotonin reuptake) is now beginning. Several new research programs were initiated and patients accrued: A collaborative program with NCI investigating the potentiation of opiate analgesia by the CCK antagonist proglumide and by desipramine; a post-operative pain program with the Bethesda Naval Hospital Department of Surgery studying the effects of pre- operative treatment with prostaglandin inhibitors on post-operative pain; and a program of detailed sensory testing to elucidate the mechanism of neuropathic pain states.